Understanding the Hidden Epidemic: Drug-Resistant Klebsiella in the Community
- Ray Sullivan
- May 12
- 5 min read
At the 2025 Theobald Smith Society Spring Symposium, the society president, Jennifer Sun, introduced Professor Barry Kreiswirth, the Theobald Smith Society 2015 Waksman Honorary Lecturer. He is a Member of the Center for Discovery and Innovation at Hackensack Meridian Health and an internationally recognized expert in microbial pathogenesis and antimicrobial resistance. Barry delivered a compelling talk that shed light on an alarming but underrecognized public health threat: the rise of multidrug-resistant Klebsiella pneumoniae infections outside hospitals. His talk, grounded in extensive genomic surveillance and cutting-edge molecular biology, emphasized that antimicrobial resistance is not just a clinical issue but an environmental and epidemiological crisis.
The Study: A Community-Centric Approach
Most surveillance studies focus on hospital-acquired infections, but Dr. Kreiswirth’s team, in collaboration with Quest Diagnostics, adopted a novel approach by sampling outpatient isolates across the U.S. Their one-year study collected over 2,000 K. pneumoniae isolates resistant to third-generation cephalosporins like ceftriaxone. Strikingly, 82% of these came from outpatient settings, and 90% were from urinary tract infections, mainly in elderly women.
What sets this study apart is its community-wide lens and real-time sequencing strategy. Instead of waiting years for results, Kreiswirth’s team aimed to complete sequencing and analysis within a year, providing timely data for public health action.
The Silent Rise of CTX-M-15
Central to the findings is the enzyme CTX-M-15, a extended-spectrum β-lactamase (ESBL) type that renders many common antibiotics ineffective. More than 90% of the isolates carried the gene encoding this enzyme. Unlike the earlier carbapenem-resistant Klebsiella epidemic driven by a single clone (ST258), this ESBL wave is genetically diverse, with over 120 distinct sequence types. This indicates a plasmid-borne epidemic, where the resistance gene spreads horizontally across unrelated strains.
CTX-M-15's widespread dissemination is driven not only by the plasmids that carry it but also by transposable elements—genetic "jumping genes"—that enable CTX-M-15 to integrate into multiple plasmid backbones. These plasmids often belong to the IncF family and are frequently conjugative, meaning they can transfer between bacteria. Many are also hybrid plasmids, which allow them to bypass incompatibility restrictions and spread even more efficiently. This dual mobility—through both plasmid conjugation and transposon-mediated transfer—explains the startling prevalence of CTX-M-15 across the U.S.
The plasmids carrying CTX-M-15 aren’t just delivering resistance to β-lactams—they’re multi-resistance vehicles. They also harbor genes conferring resistance to quinolones, aminoglycosides, sulfonamides, and even environmental toxins like arsenic, copper, and silver.
Clinical Implications: An Oral Antibiotic Crisis
One of the study’s most disturbing insights is the ineffectiveness of oral antibiotics for treating these infections. Resistance to fluoroquinolones, Bactrim, and Nitrofurantoin was prevalent in over 75% of isolates. This leaves few oral treatment options—primarily Fosfomycin, which itself is compromised in many strains. As a result, patients may increasingly require injectable therapy for what were once easily managed infections.
In the face of such resistance, pharmaceutical companies have devised creative ways to restore the utility of β-lactams. One such approach is the use of β-lactamase inhibitors like avibactam. When paired with the third-generation cephalosporin ceftazidime, avibactam neutralizes many ESBL enzymes, allowing the antibiotic to work again. This combination, known as ceftazidime-avibactam, has been a game changer against certain resistant strains.
Another innovation is cefiderocol, a novel cephalosporin that exploits bacterial iron uptake systems. By linking the drug to a siderophore—a molecule bacteria recognize and import for iron scavenging—cefiderocol acts as a “Trojan horse,” sneaking the antibiotic into the cell. This clever strategy has shown promise against carbapenem-resistant organisms, though its use is currently limited to serious hospital-acquired infections.
Plasmids: Survival Machines Beyond the Clinic
Kreiswirth emphasized that these plasmids are not just clinical nuisances but ecological survivors. His team used long-read sequencing (Nanopore) to fully resolve dozens of plasmids, revealing a staggering arsenal of survival genes: heat resistance, iron acquisition systems, and resistance to heavy metals. These features suggest that the plasmids are optimized not just for drug resistance but also for enduring harsh environmental conditions.
Plasmid-borne heat resistance, in particular, stood out. By knocking out heat resistance genes and curing the plasmids from Klebsiella strains, Kreiswirth's lab demonstrated that survival at elevated temperatures dramatically declined. This implies that the plasmids’ benefits go well beyond the hospital setting—they provide ecological advantages that help the host bacteria persist in environments like wastewater, soil, or agriculture.
A 2024 study from Norway underscored this point, finding an identical resistance plasmid in a Klebsiella isolate from a sewage treatment plant. This discovery points to the environment—not hospitals—as the true battleground of resistance evolution.
CRISPR Tools Reveal Plasmid Power
To demonstrate the direct role of these plasmids in resistance and survival, Kreiswirth’s lab used CRISPR to remove them from bacterial strains precisely. The results were dramatic: susceptibility to antibiotics was restored, and environmental resilience (to heat and low iron) was diminished. Further experiments knocked out individual genes, proving CTX-M-15’s central role in β-lactam resistance and suggesting that other uncharacterized genes likely play critical roles.
These tools not only illuminate cause-and-effect relationships but also offer a platform for functional genomics. By selectively restoring or deleting plasmid genes, the team can map which traits confer survival, which confer resistance, and how they interact with chromosomal elements like efflux pumps or resistance-conferring mutations.
Rethinking Resistance
Dr. Kreiswirth concluded with a provocative assertion: we may be misunderstanding the purpose of antibiotic resistance. Rather than being a side effect of medical antibiotic use, resistance mechanisms may primarily support environmental survival, with pathogenicity being a coincidental byproduct. Antibiotic residues in wastewater and environmental niches only reinforce this possibility.
In sum, Kreiswirth’s talk challenged attendees to think beyond the hospital ward. As antimicrobial resistance continues to evolve, he urged the microbiology community to prioritize surveillance, expand environmental research, and reconsider how we frame resistance—not just as a medical emergency, but as an ecological phenomenon.
After the talk, Barry had the opportunity to meet Rutgers Professor Nicole Fahrenfeld who studies antibiotics and antibiotic resistant bacteria in sewer systems. They may now collaborate on environmental surveillance of drug-resistant Klebsiella pneumoniae as well as other antibiotic resistant bacteria.
You can watch Professor Kreiswirth’s talk at https://youtu.be/RKxTGqUPcuw
References
Jiang J, Long T, Porter AR, Lovey A, Lee A, Jacob JT, Arias CA, Bonomo R, Kalayjian R, Zhao Y, DeLeo FR, van Duin D, Kreiswirth BN, Chen L. Carbapenem-Resistant, Virulence Plasmid-Harboring Klebsiella pneumoniae, United States. Emerg Infect Dis. 2025 Apr;31(4):761-771. doi: 10.3201/eid3104.241396. Epub 2024 Mar 12. PMID: 40072602; PMCID: PMC11950267.
Wei J, Huang J, Zou C, Shen S, Kreiswirth BN, Huang A, Huang S, Chen L, Wang D, Niu S. Diverse evolutionary trajectories of Klebsiella pneumoniae carbapenemase: unraveling the impact of amino acid substitutions on β-lactam susceptibility and the role of avibactam in driving resistance. mSystems. 2025 Apr 22;10(4):e0018425. doi: 10.1128/msystems.00184-25. Epub 2025 Mar 11. PMID: 40067047; PMCID: PMC12013264.
Jiang J, Cienfuegos-Gallet AV, Long T, Peirano G, Chu T, Pitout JDD, Kreiswirth BN, Chen L. Intricate interplay of CRISPR-Cas systems, anti-CRISPR proteins, and antimicrobial resistance genes in a globally successful multi-drug resistant Klebsiella pneumoniae clone. Genome Med. 2025 Jan 30;17(1):9. doi: 10.1186/s13073-025-01428-6. Erratum in: Genome Med. 2025 Feb 24;17(1):13. doi: 10.1186/s13073-025-01436-6. PMID: 39885543; PMCID: PMC11781037.
Yen KK, Terlecky AJ, Hao M, Cienfuegos V, Rojtman A, Chen L, Kreiswirth BN. Curing of common plasmids in gram-negative bacteria using a Cas9-based conjugative vector. J Microbiol Methods. 2024 Nov;226:107047. doi: 10.1016/j.mimet.2024.107047. Epub 2024 Sep 18. PMID: 39303991.
Excellent presentation and write-up.